This request for a continuation of support is for longitudinal research designed to reveal basic principles and cellular mechanisms underlying development of the primate nervous system. In the next cycle of this grant, emphasis will be on (1) mechanisms of neuronal migration that include identification of binding molecule(s) and relative speed of cell translocation under normal and altered conditions; (2) the determinants of cell phenotypes and emergence of cytochemical individuality of neurons in developing primate brain under normal and experimentally altered conditions; (3) the capacity for postdevelopmental neurogenesis in primates; (4) development of synaptic connectivity and biochemical maturation of the "extrapyramidal" motor system in developing normal monkeys and monkeys lesioned at critical embryonic ages; and (5) correlation of critical developmental periods as defined in experimental studies on developing monkey with corresponding stages based on various morphological and cytochemical criteria applied in postmortem human fetal brain. Each Specific Aim consists of several interrelated experiments designed to use a battery of various light, electronmicroscopic and immunocytochemical methods including Golgi impregnation, Nissl-stain, histochemistry (e.g., AChE, monoamine fluorescence), immunocytochemistry (using a variety of antibodies), 3H-TdR autoradiography, anterograde and/or retrograde transport of radioactive tracers, HRP, or various fluorescent dyes. Our ability to perform intrauterine neurosurgery with short and long survival periods not only provides an opportunity to study the emergence of connections, but to change connectivity and explore experimentally the role of cell-to-cell interaction in morphological and biochemical maturation of the central nervous system. Until recently, experimental manipulation of early developmental processes has been the domain of research in simpler and peripheral nervous systems. In this project, as in the past, all studies will be performed on the developing rhesus monkey, with the conviction that the results will contribute to a greater understanding of mechanisms in normal brain development and help to uncover the etiology and pathogenesis of developmental brain disorders in man.